Avycaz Drug Information

Recommended Dosage in Pediatric Patients

The recommended dosage of AVYCAZ in pediatric patients aged 2 years to less than 18 years and an estimated glomerular filtration rate (eGFR) greater than 50 mL/min/1.73 m 2 and in pediatric patients less than 2 years of age without renal impairment is described in Table 2. AVYCAZ is administered every 8 hours by intravenous infusion over 2 hours. For treatment of cIAI, metronidazole should be given concurrently. *AVYCAZ was used in conjunction with metronidazole 10 mg/kg intravenously every 8 hours in pediatric cIAI patients a For pediatric patients (aged 2 years and older) with eGFR less than or equal to 50 mL/min/1.73m 2, dosage adjustments are recommended. b Includes full-term infants with PNA > 28 days and pre-term infants with corrected age > 28 days.

GA = gestational age and PNA = postnatal age.

Dosage Adjustments in Adult and Pediatric Patients ( Aged 2 Years and Older) with Renal Impairment The recommended AVYCAZ dosage in adult and pediatric patients aged 2 years and older with varying degrees of renal function is presented in Table 3 and Table 4, respectively. For patients with changing renal function, monitor CrCl in adults or eGFR in pediatric patients at least daily and adjust the dosage of AVYCAZ accordingly. There is insufficient information to recommend a dosing regimen for pediatric patients less than 2 years of age with renal impairment.

Adult Patients a Dosing was derived based on the population PK modeling, which assumed similar proportional effects of renal impairment in adults and pediatric patients aged 2 years and older b As calculated using the Schwartz bedside formula c All doses of AVYCAZ are administered over 2 hours d Both ceftazidime and avibactam are hemodialyzable; thus, administer AVYCAZ after hemodialysis on hemodialysis days 2. 4 Preparation of the AVYCAZ Solution for Administration AVYCAZ is supplied as a dry powder, which must be constituted and subsequently diluted, using aseptic technique prior to intravenous infusion. a Constitute the powder in the AVYCAZ vial with 10 mL of one of the following solutions: sterile water for injection, USP 0.9% of sodium chloride injection, USP (normal saline) 5% of dextrose injection, USP all combinations of dextrose injection and sodium chloride injection, USP, containing up to 2.5% dextrose, USP, and 0.45% sodium chloride, USP, or lactated Ringer’s injection, USP b Mix gently and ensure that the contents are dissolved completely. The constituted AVYCAZ solution will have an approximate ceftazidime concentration of 167 mg/mL and an approximate avibactam concentration of 42 mg/mL. The final volume is approximately 12 mL.

The constituted solution is not for direct injection. The constituted solution must be diluted before intravenous infusion. c Prepare the required dose for intravenous infusion by withdrawing the appropriate volume determined from Table 5 from the constituted vial. To prepare doses for pediatric patients weighing less than 40 kg, follow the constitution instruction above to yield a solution with a final AVYCAZ concentration of approximately 209 mg/mL (ceftazidime concentration of 167 mg/mL and an avibactam concentration of 42 mg/mL).

Use these concentrations to calculate the volume of AVYCAZ required to prepare the prescribed dose. d Before infusion, dilute the withdrawn volume of the constituted AVYCAZ solution further with the same diluent used for constitution of the powder (except sterile water for injection), to achieve a ceftazidime concentration of 8 to 40 mg/mL and an avibactam concentration of 2 to 10 mg/mL in an infusion bag. If sterile water for injection was used for constitution, use any of the other appropriate constitution diluents for dilution. e Mix gently and ensure that the contents are dissolved completely. Visually inspect the diluted AVYCAZ solution (for administration) for particulate matter and discoloration prior to administration (the color of the AVYCAZ infusion solution for administration ranges from clear to light yellow). f Use the diluted AVYCAZ solution in the infusion bags within 12 hours when stored at room temperature. g The diluted AVYCAZ solution in the infusion bags may be stored under refrigeration at 2 to 8°C (36 to 46°F) up to 24 hours following dilution and used within 12 hours of subsequent storage at room temperature. 2. 5 Drug Compatibility The AVYCAZ solution for administration at the range of diluted concentrations of ceftazidime 8 mg/mL and avibactam 2 mg/mL to ceftazidime 40 mg/mL and avibactam 10 mg/mL is compatible with the more commonly used intravenous infusion fluids in infusion bags (including Baxter ® Mini-Bag Plus ™ ) such as: 0.9% sodium chloride injection, USP 5% dextrose injection, USP all combinations of dextrose injection and sodium chloride injection, USP, containing up to 2.5% dextrose, USP, and 0.45% sodium chloride, USP lactated ringer's injection, USP, and Baxter ® Mini-Bag Plus ™ containing 0.9% sodium chloride injection or 5% dextrose injection Intravenous Line Compatibility Simulated Y-site compatibility of AVYCAZ admixed with other drug products in a 1:1 volume ratio at room temperature was evaluated by visual inspection, and measurement of turbidity and particulate matter at 0, 1 and 4 hours after mixing.

Ceftazidime and avibactam were tested at concentrations of 20 mg/mL and 5 mg/mL, respectively, which can be obtained by dilution of constituted AVYCAZ solution in a 100 mL intravenous infusion bag. The highest recommended concentration (40 mg/mL of ceftazidime and 10 mg/mL of avibactam) was not tested in this study and should not be used during co-administration of AVYCAZ with other drugs through the same intravenous line. Compatible drugs with the corresponding compatible diluent (i.e., 0.9% Sodium Chloride Injection, 5 % Dextrose Injection or Lactated Ringer’s Injection) are listed in Tables below.

Any drug products not listed in the tables below should not be co-administered with AVYCAZ through the same intravenous line (or cannula). 2. 6 St orage of Constituted Solutions Upon constitution with appropriate diluent, the constituted AVYCAZ solution may be held for no longer than 30 minutes prior to transfer and dilution in a suitable infusion bag. Following dilution of the constituted solutions with the appropriate diluents, AVYCAZ solutions in the infusion bags are stable for 12 hours when stored at room temperature. Following dilution of the constituted solutions with the appropriate diluents, AVYCAZ solutions in the infusion bags may also be refrigerated at 2 to 8°C (36 to 46°F) for up to 24 hours; and then should be used within 12 hours of subsequent storage at room temperature.

Clinical

Trial s Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Clinical Trials Experience in Adult Patients AVYCAZ was evaluated in six active-controlled clinical trials in patients with cIAI, cUTI, including pyelonephritis, or HABP/VABP. These trials included two Phase 2 trials, one in cIAI and one in cUTI, as well as four Phase 3 trials, one in cIAI, one in cUTI (Trial 1), one in cIAI or cUTI due to ceftazidime non-susceptible pathogens (Trial 2), and one in HABP/VABP.

Data from cUTI Trial 1 served as the primary dataset for AVYCAZ safety findings in cUTI as there was a single comparator. cUTI Trial 2 had an open-label design as well as multiple comparator regimens which prevented pooling but provided supportive information. The six clinical trials included a total of 1809 adult patients treated with AVYCAZ and 1809 patients treated with comparators. Patients were predominantly male (62%) and Caucasian (76.6%).

Adverse reactions occurring at 5% or greater in patients receiving AVYCAZ plus metronidazole were diarrhea, nausea, and vomiting. Table 11 lists adverse reactions occurring in 1% or more of patients receiving AVYCAZ plus metronidazole and with incidences greater than the comparator in the Phase 3 cIAI clinical trial. Within this subgroup, patients treated with AVYCAZ received a 33% lower daily dose than is currently recommended for patients with CrCl 30 to less than or equal to 50 mL/min.

The causes of death varied and contributing factors included progression of underlying infection, baseline pathogens isolated that were unlikely to respond to the study drug, and delayed surgical intervention. Patients were predominantly female (68.3%) and Caucasian (82.4%). Patients with CrCl less than 30 mL/min were excluded.

There were no deaths in Trial 1. The most common adverse reactions occurring in 3% of cUTI patients treated with AVYCAZ were nausea and diarrhea. Patients were predominantly male (74.5%) and Asian (56.2%).

Table 13 lists selected adverse reactions occurring in 1% or more of patients receiving AVYCAZ and with incidences greater than the comparator in the Phase 3 HABP/VABP clinical trial. of AVYCAZ and Ceftazidime in Adults Direct Coombs’ Test Seroconversion with AVYCAZ In the Phase 3 trials, seroconversion from a negative to a positive direct Coombs’ test result among patients with an initial negative Coombs’ test and at least one follow up test occurred in 3% (cUTI), 12.9% (cIAI), and 21.4% (HABP/VABP) of patients receiving AVYCAZ and 0.9% (cUTI), 3% (cIAI) and 7% (HABP/VABP) of patients receiving a carbapenem comparator. Less Common Adverse Reactions with AVYCAZ The following selected adverse reactions were reported in AVYCAZ-treated patients at a rate of less than 1% in the Phase 3 trials and are not described elsewhere in the labeling. Blood and lymphatic disorders – Thrombocytopenia, Thrombocytosis, Leukopenia General disorders and administration site conditions – Injection site phlebitis Infections and infestations – Candidiasis Investigations – Increased aspartate aminotransferase, Increased alanine aminotransferase, Increased gamma-glutamyl transferase Metabolism and nutrition disorders – Hypokalemia Nervous system disorders – Dysgeusia Renal and urinary disorders – Acute kidney injury, Renal impairment, Nephrolithiasis Skin and subcutaneous tissue disorders – Rash, Rash maculo-papular, Urticaria Psychiatric disorders – Anxiety Adverse Reactions with Ceftazidime Additionally, adverse reactions reported with ceftazidime alone that were not reported in AVYCAZ-treated patients in the Phase 3 trials are listed below: Blood and lymphatic disorders – Agranulocytosis, Hemolytic anemia, Lymphocytosis, Neutropenia, Eosinophilia General disorders and administration site conditions – Infusion site inflammation, Injection site hematoma, Injection site thrombosis Hepatobiliary disorders – Jaundice Investigations – Increased blood lactate dehydrogenase, Prolonged prothrombin time Nervous system disorders – Paresthesia, seizures, encephalopathy, coma, asterixis, neuromuscular excitability, myoclonia Renal and urinary disorders – Tubulointerstitial nephritis Reproductive and breast disorders – Vaginal inflammation Hypersensitivity Reactions – Anaphylaxis, Angioedema, Erythema multiforme, Stevens-Johnson syndrome, Toxic epidermal necrolysis Clinical Trials Experience in Pediatric Patients Pediatric Patients A ged 3 months to less than 18 years AVYCAZ was evaluated in 128 pediatric patients aged 3 months to < 18 years in two single-blind, randomized, active-controlled clinical trials, one in patients with cUTI and the other in patients with cIAI.

Safety data from the two studies were pooled. The AVYCAZ dosing regimen was the same in both of these trials with a mean treatment duration of 6 days, and a maximum of 14 days. The regimen was selected to result in pediatric drug exposure comparable to that of adults, and in the cIAI trial, metronidazole was administered concurrently with AVYCAZ.

Patients were randomized 3:1 to receive AVYCAZ or comparator, which was meropenem or cefepime in the cIAI and cUTI trials, respectively. The median age of patients treated with AVYCAZ was 8.6 years, and in the comparator group 7.4 years. The majority of patients treated with AVYCAZ were female (57%) and Caucasian (80%).

An open-label single-dose pharmacokinetic (PK) and safety trial was conducted in pediatric patients with HABP/VABP and enrolled four patients aged 11.6 months to 9.4 years. There were no deaths reported in the trials of cUTI, cIAI, and HABP/VABP in pediatric patients aged 3 months and older. Treatment discontinuation due to adverse reactions in the pediatric cUTI and cIAI trials occurred in 2.3% (3/128) of patients receiving AVYCAZ and 0/50 of patients receiving comparator drugs.

The most common adverse reactions occurring in greater than 3% of pediatric patients aged 3 months to < 18 years treated with AVYCAZ were vomiting, diarrhea, rash, and infusion site phlebitis. The median age of patients treated with AVYCAZ was 24 days. In this single-arm trial, 25 patients with a suspected or confirmed bacterial infection received a single-dose of AVYCAZ and 21 patients with suspected or confirmed serious gram-negative infections received multiple doses of AVYCAZ.

In patients treated with multiple doses of AVYCAZ, the mean treatment duration was 6 days and maximum treatment duration was 12 days. There was one death reported in the trial for pediatric patients less than 3 months of age. There were no treatment discontinuations due to adverse reactions.

The most common adverse reactions occurring in greater than 3% of pediatric patients less than 3 months of age were vomiting and increased transaminases. The safety profile of AVYCAZ in pediatric patients was similar to adults with cIAI, cUTI, and HABP/VABP treated with AVYCAZ.

Postmarketing Experience

The following adverse reactions and altered laboratory tests have been identified during post approval use of ceftazidime (a component of AVYCAZ), or other cephalosporin-class antibacterial drugs. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Colitis, toxic nephropathy, hepatic dysfunction including cholestasis, hemorrhage, pancytopenia, aplastic anemia, prolonged prothrombin time, false-positive test for urinary glucose.

Acute myocardial ischemia with or without myocardial infarction may occur as part of an allergic reaction.

Probenecid

In vitro, avibactam is a substrate of OAT1 and OAT3 transporters which might contribute to the active uptake from the blood compartment, and thereby its excretion. As a potent OAT inhibitor, probenecid inhibits OAT uptake of avibactam by 56% to 70% in vitro and, therefore, has the potential to decrease the elimination of avibactam when co-administered. Because a clinical interaction study of AVYCAZ or avibactam alone with probenecid has not been conducted, co-administration of AVYCAZ with probenecid is not recommended.

Drug/Laboratory Test Interactions

The administration of ceftazidime may result in a false-positive reaction for glucose in the urine with certain methods. It is recommended that glucose tests based on enzymatic glucose oxidase reactions be used.

Pregnancy Risk Summary There are no adequate and well-controlled studies of AVYCAZ, ceftazidime, or avibactam in pregnant women. Neither ceftazidime nor avibactam were teratogenic in rats at doses 40 and 9 times the recommended human clinical dose. In the rabbit, at twice the exposure as seen at the human clinical dose, there were no effects on embryofetal development with avibactam.

The background risk of major birth defects and miscarriage for the indicated population is unknown. The background risk of major birth defects is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies within the general population. Because animal reproduction studies are not always predictive of human response, this drug should be used in pregnancy only if clearly needed.

Data Animal Data Ceftazidime Reproduction studies have been performed in mice and rats at doses up to 40 times the human dose and showed no evidence of harm to the fetus due to ceftazidime. Avibactam Avibactam was not teratogenic in rats or rabbits. In the rat, intravenous studies with mg/kg/day avibactam during gestation days 6-17 showed no embryofetal toxicity at doses up to 1000 mg/kg/day, approximately 9 times the human dose based on exposure (AUC).

In a rat pre- and post-natal study at up to 825 mg/kg/day intravenously (11 times the human exposure based on AUC), there were no effects on pup growth and viability. A dose-related increase in the incidence of renal pelvic and ureter dilatation was observed in female weaning pups that was not associated with pathological changes to renal parenchyma or renal function, with renal pelvic dilatation persisting after female weaning pups became adults. Rabbits administered intravenous avibactam on gestation days mg/kg/day showed no effects on embryofetal development at a dose of 100 mg/kg, twice the human exposure (AUC).

At higher doses, increased post-implantation loss, lower mean fetal weights, delayed ossification of several bones and other anomalies were observed.

Pediatric Use The safety and effectiveness of AVYCAZ in the treatment of cUTI, cIAI, and HABP/VABP have been established in pediatric patients at least 31 weeks gestational age and older. Use of AVYCAZ is supported by evidence from adequate and well-controlled studies of AVYCAZ in adults with cUTI, cIAI, and HABP/VABP and additional pharmacokinetic and safety data from pediatric trials. The safety profile of AVYCAZ in pediatric patients was similar to adults with cIAI, cUTI, and HABP/VABP treated with AVYCAZ.

The safety and effectiveness of AVYCAZ in the treatment of cUTI, cIAI, and HABP/VABP have not been established in pediatric patients less than 31 weeks gestational age.

AVYCAZ is contraindicated in patients with known serious hypersensitivity to the components of AVYCAZ (ceftazidime and avibactam), avibactam containing products, or other members of the cephalosporin class.

In the event of overdose, discontinue AVYCAZ and institute general supportive treatment. Ceftazidime and avibactam can be removed by hemodialysis. In subjects with end-stage renal disease (ESRD) administered 1 gram ceftazidime, the mean total recovery in dialysate following a 4-hour hemodialysis session was 55% of the administered dose.

In subjects with ESRD administered 100 mg avibactam, the mean total recovery in dialysate following a 4-hour hemodialysis session started 1 hour after dosing was approximately 55% of the dose. No clinical information is available on the use of hemodialysis to treat AVYCAZ overdosage.